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Abstract
Busulfan is an alkylating agent widely used in high-dose chemotherapy regimens for hematopoietic stem cell transplantation or bone marrow transplantation. Busulfan in blood has been shown to be an important determinant of graft rejection and regimen-related toxicity. In order to assess the safety and efficacy of high-dose busulfan, a sensitive analytical method is needed. An assay by gas chromatography-mass spectrometry (GC-MS) in negative-ion chemical ionization (NCI) mode capable of measuring lower concentration of busulfan in human serum was developed. An internal standard, 1,3-bis (methansulfonyloxy)propane, was synthesized. Busulfan and internal standard in serum were directly derivatized with sodium iodide, and the resulted diiodo-derivatives were analyzed by GC-MS-NCI mode with methane as the reagent gas. In the NCI mode the monitored ion was focused at m/z 127 for derivatives from busulfan and internal standard. The negative ions correspond to the iodine atom. Chromatographic separation was achieved on a capillary column using helium as the carrier gas. The assay was linear from 0.1 to 1000 ng/ml. The intra-assay precision for busulfan was 6.6 % at 50 ng/ml. The assay possessed linearity up to 0.1ng/ml, sensitivity to at least 20 pg/ml, average recovery of 93 %. Furthermore, the assay correlated highly with a validated GC-MS in electron impact mode. The method was used to determine busulfan in serum samples collected during and after multiple 1.25 mg/kg oral doses of busulfan. A terminal concentration of 0.61 ng/ml of busulfan was detected at 38 h following the last dose. The determination by GC-MS-NCI mode of diiodo-derivative from busulfan will facilitate analysis of both small volume of pediatric serum sample and small amounts of busulfan in samples of terminal elimination phase.